Center for Innovation in Molecular and Pharmaceutical Sciences (CIMPS), Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Amity Institute of Biotechnology, Amity University, Kolkata 700135, India.
Amity Institute of Biotechnology, Amity University, Kolkata 700135, India.
Biochim Biophys Acta Mol Basis Dis. 2022 Nov 1;1868(11):166514. doi: 10.1016/j.bbadis.2022.166514. Epub 2022 Aug 4.
Acquiring the human ACE2 receptor usage trait enables the coronaviruses to spill over to humans. However, the origin of the ACE2 usage trait in coronaviruses is poorly understood. Using a multi-disciplinary approach combining evolutionary bioinformatics and molecular dynamics simulation, we decode the principal driving force behind human ACE2 receptor recognition in coronaviruses. Genomic content, evolutionary divergence, and codon usage bias analysis reveal that SARS-CoV2 is evolutionarily divergent from other human ACE2-user CoVs, indicating that SARS-CoV2 originates from a different lineage. Sequence analysis shows that all the human ACE2-user CoVs contain two insertions in the receptor-binding motif (RBM) that directly interact with ACE2. However, the insertion sequences in SARS-CoV2 are divergent from other ACE2-user CoVs, implicating their different recombination origins. The potential of mean force calculations reveals that the high binding affinity of SARS-CoV2 RBD to human ACE2 is primarily attributed to its ability to form a higher number of hydrogen bonds than the other ACE2-user CoVs. The adaptive branch-site random effects likelihood method identifies positive selection bias across the ACE2 user CoVs lineages. Recombination and selection forces shape the spike evolution in human ACE2-using beta-CoVs to optimize the interfacial hydrogen bonds between RBD and ACE2. However, these evolutionary forces work within the constraints of nucleotide composition, ensuring optimum codon adaptation of the spike (S) gene within the host cell.
获得人类 ACE2 受体使用特性使冠状病毒能够溢出到人类身上。然而，冠状病毒中 ACE2 使用特性的起源还知之甚少。本研究采用结合进化生物信息学和分子动力学模拟的多学科方法，解码冠状病毒中人类 ACE2 受体识别的主要驱动力。基因组内容、进化分歧和密码子使用偏性分析表明，SARS-CoV-2 与其他人类 ACE2-使用者冠状病毒在进化上存在分歧，这表明 SARS-CoV-2 起源于不同的谱系。序列分析表明，所有人类 ACE2-使用者冠状病毒的受体结合基序（RBM）中都包含两个与 ACE2 直接相互作用的插入序列。然而，SARS-CoV-2 中的插入序列与其他 ACE2-使用者冠状病毒不同，暗示它们有不同的重组起源。平均力计算表明，SARS-CoV-2 RBD 与人 ACE2 高结合亲和力主要归因于其形成比其他 ACE2-使用者冠状病毒更多氢键的能力。适应性分支位点随机效应似然法鉴定了 ACE2 用户冠状病毒谱系中的正选择偏向。重组和选择力量塑造了人类 ACE2 使用的β-冠状病毒的刺突进化，以优化 RBD 和 ACE2 之间的界面氢键。然而，这些进化力量在核苷酸组成的限制内发挥作用，确保了宿主细胞中刺突（S）基因的最佳密码子适应。
